Expression Of lncRNA MALAT1 Research Articles

Regulation of mitochondrial autophagy by lncRNA MALAT1 in sepsis-induced myocardial injury

BackgroundSepsis-induced myocardial injury (SIMI) is a severe complication of sepsis, contributing significantly to mortality. Mitochondrial dysfunction and dysregulated autophagy are implicated in SIMI pathogenesis. Long non-coding RNA MALAT1 has been associated with various diseases, including sepsis, but its role in SIMI remains unclear.ObjectiveThis study aimed to investigate the role of lncRNA MALAT1 in SIMI, specifically in the regulation of mitochondrial autophagy.MethodsA sepsis-induced cardiomyopathy model was established in mice, and the cardiac tissues were analyzed. The expression of lncRNA MALAT1 was modulated and its effects on mitochondrial autophagy, myocardial injury, inflammation, and apoptosis were assessed. Furthermore, the interaction between MALAT1 and miR-146a was explored, as well as the involvement of the TLR4/NF-kB/MAPK signaling pathway.ResultsActivation of mitochondrial autophagy by urolithin A (UA) alleviated SIMI, inflammation, and cardiac dysfunction. Downregulation of MALAT1 enhanced mitochondrial autophagy, stabilized the mitochondrial membrane potential, and inhibited mitochondrial reactive oxygen species (ROS) production, leading to improved cell viability and reduced myocardial injury. Furthermore, MALAT1 interacted with miR-146a, and their modulation influenced mitochondrial autophagy, myocardial injury, and inflammation. The TLR4/NF-kB/MAPK signaling pathway was implicated in these processes.ConclusionOur findings suggest that lncRNA MALAT1 plays a crucial role in SIMI by modulating miR-146a-mediated mitochondrial autophagy and the TLR4/NF-kB/MAPK signaling pathway. These results provide new insights into the pathogenesis of SIMI and potential therapeutic targets.

Roles of lncRNA-MALAT1 in the Progression and Prognosis of Gliomas.

Long noncoding RNAs (lncRNAs) represent a large subgroup of RNA transcripts that lack the function of coding proteins and may be essential universal genes involved in carcinogenesis and metastasis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNAMALAT1) is overexpressed in various human tumors, including gliomas. However, the biological function and molecular mechanism of action of lncRNA-MALAT1 in gliomas have not yet been systematically elucidated. Accumulating evidence suggests that the abnormal expression of lncRNA-MALAT1 in gliomas is associated with various physical properties of the glioma, such as tumor growth, metastasis, apoptosis, drug resistance, and prognosis. Furthermore, lncRNAs, as tumor progression and prognostic markers in gliomas, may affect tumorigenesis, proliferation of glioma stem cells, and drug resistance. In this review, we summarize the knowledge on the biological functions and prognostic value of lncRNA-MALAT1 in gliomas. This mini-review aims to deepen the understanding of lncRNA-MALAT1 as a novel potential therapeutic target for the individualized precision treatment of gliomas.

The relationship between the expression of lncRNA MALAT1 and clinical features and prognosis in bladder cancer: A meta-analysis.

The objective of this meta-analysis is to evaluate the association between LncRNA MALAT1 and the clinicopathological characteristics and prognosis in patients with bladder cancer. Related studies were searched from Pubmed, Embase, Cochrane Library, CNKI and Web of Science up to Sep 1, 2021. Basic characteristic and prognostic data were extracted from the included studies. We synthesized and compared primary outcomes such as overall survival. Based on the cut-off value, sample size, and follow-up time, subgroup analysis was conducted. We calculated the combined hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) to assess the relationship between LncRNA MALAT1 and prognosis clinicopathological features of bladder cancer patients. Seven studies with 822 patients were included in this meta-analysis. The results showed that the high lncRNA MALAT1 was significantly related to poor overall survival (HR = 2.34, 95% CI:1.61-3.38; P<0.001) in bladder cancer patients. Furthermore, a high level of LNCRNA MALAT1 is associated with lymph node metastasis (LNM) (OR = 1.82, 95% CI 1.32-2.52, P <0.001) in bladder cancer. The results of sensitivity analysis showed the stabilization and reliability of results in this Meta-analysis. In conclusion, elevated LncRNA MALAT1 is associated with a poor prognosis and a higher risk of LNM in patients with bladder cancer. LncRNA MALAT1 could be identified as a biomarker with a potential prognostic value in bladder cancer.

LncRNA Malat1 regulates iPSC-derived β-cell differentiation by targeting the miR-15b-5p/Ihh axis

BackgroundDifferentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory mechanisms of long noncoding RNAs (lncRNAs) in β-like cells derived from iPSCs is important for understanding the development of the pancreas and pancreatic β-cells and may improve the quality of β-like cells for stem cell therapy. Methodsβ-like cells were derived from iPSCs in a three-step protocol. RNA sequencing and bioinformatics analysis were carried out to screen the differentially expressed lncRNAs and identify the putative target genes separately. LncRNA Malat1 was chosen for further research. Series of loss and gain of functions experiments were performed to study the biological function of LncRNA Malat1. Quantitative real-time PCR (qRT-PCR), Western blot (WB) analysis and immunofluorescence (IF) staining were carried out to separately detect the functions of pancreatic β-cells at the mRNA and protein levels. Cytoplasmic and nuclear RNA fractionation and fluorescence in situ hybridization (FISH) were used to determine the subcellar location of lncRNA Malat1 in β-like cells. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the differentiation and insulin secretion of β-like cells after stimulation with different glucose concentrations. Structural interactions between lncRNA Malat1 and miR-15b-5p and between miR-15b-5p/Ihh were detected by dual luciferase reporter assays (LRAs). ResultsWe found that the expression of lncRNA Malat1 declined during differentiation, and overexpression (OE) of lncRNA Malat1 notably impaired the differentiation and maturation of β-like cells derived from iPSCs in vitro and in vivo. Most importantly, lncRNA Malat1 could function as a competing endogenous RNA (ceRNA) of miR-15b-5p to regulate the expression of Ihh according to bioinformatics prediction, mechanistic analysis and downstream experiments. ConclusionThis study established an unreported regulatory network of lncRNA Malat1 and the miR-15b-5p/Ihh axis during the differentiation of iPSCs into β-like cells. In addition to acting as an oncogene promoting tumorigenesis, lncRNA Malat1 may be an effective and novel target for treatment of diabetes in the future.

Knockdown of lncRNA MALAT1 attenuates renal interstitial fibrosis through miR-124-3p/ITGB1 axis

Renal interstitial fibrosis (RIF) considered the primary irreversible cause of chronic kidney disease. Recently, accumulating studies demonstrated that lncRNAs play an important role in the pathogenesis of RIF. However, the underlying exact mechanism of lncRNA MALAT1 in RIF remains barely known. Here, the aim of our study was to investigate the dysregulate expression of lncRNA MALAT1 in TGF-β1 treated HK2/NRK-49F cells and unilateral ureteral obstruction (UUO) mice model, defining its effects on HK2/NRK-49F cells and UUO mice fibrosis process through the miR-124-3p/ITGB1 signaling axis. It was found that lncRNA MALAT1 and ITGB1 was significantly overexpression, while miR-124-3p was downregulated in HK2/NRK-49F cells induced by TGF-β1 and in UUO mice model. Moreover, knockdown of lncRNA MALAT1 remarkably downregulated the proteins level of fibrosis-related markers, ITGB1, and upregulated the expression of epithelial marker E-cadherin. Consistently, mechanistic studies showed that miR-124-3p can directly binds to lncRNA MALAT1 and ITGB1. And the protect effect of Len-sh-MALAT1 on fibrosis related protein levels could be partially reversed by co-transfected with inhibitor-miR-124-3p. Moreover, the expression trend of LncRNA MALAT1/miR-124-3p/ITGB1 in renal tissues of patients with obstructive nephropathy (ON) was consistent with the results of cell and animal experiments. Taken together, these results indicated that lncRNA MALAT1 could promote RIF process in vitro and in vivo via the miR-124-3p/ITGB1 signaling pathway. These findings suggest a new regulatory pathway involving lncRNA MALAT1, which probably serves as a potential therapeutic target for RIF.

Pomegranate peel extract protects against the development of diabetic cardiomyopathy in rats by inhibiting pyroptosis and downregulating LncRNA-MALAT1.

Background: Pyroptosis is an inflammatory programmed cell death accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Pyroptosis is closely linked to the development of diabetic cardiomyopathy (DC). Pomegranate peel extract (PPE) exhibits a cardioprotective effect due to its antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanisms of the protective effect of PPE on the myocardium in a rat model of DC and determine the underlying molecular mechanism. Methods: Type 1 diabetes (T1DM) was induced in rats by intraperitoneal injection of streptozotocin. The rats in the treated groups received (150mg/kg) PPE orally and daily for 8weeks. The effects on the survival rate, lipid profile, serum cardiac troponin-1, lipid peroxidation, and tissue fibrosis were assessed. Additionally, the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue was determined. The PPE was analyzed using UPLC-MS/MS and NMR for characterizing the phytochemical content. Results: Prophylactic treatment with PPE significantly ameliorated cardiac hypertrophy in the diabetic rats and increased the survival rate. Moreover, prophylactic treatment with PPE in the diabetic rats significantly improved the lipid profile, decreased serum cardiac troponin-1, and decreased lipid peroxidation in the myocardial tissue. Histopathological examination of the cardiac tissues showed a marked reduction in fibrosis (decrease in collagen volume and number of TGF-β-positive cells) and preservation of normal myocardial structures in the diabetic rats treated with PPE. There was a significant decrease in the expression of pyroptosis-related genes (NLRP3 and caspase-1) and lncRNA-MALAT1 in the heart tissue of the diabetic rats treated with PPE. In addition, the concentration of IL-1β and caspase-1 significantly decreased in the heart tissue of the same group. The protective effect of PPE on diabetic cardiomyopathy could be due to the inhibition of pyroptosis and downregulation of lncRNA-MALAT1. The phytochemical analysis of the PPE indicated that the major compounds were hexahydroxydiphenic acid glucoside, caffeoylquinic acid, gluconic acid, citric acid, gallic acid, and punicalagin. Conclusion: PPE exhibited a cardioprotective potential in diabetic rats due to its unique antioxidant, anti-inflammatory, and antifibrotic properties and its ability to improve the lipid profile. The protective effect of PPE on DC could be due to the inhibition of the NLRP3/caspase-1/IL-1β signaling pathway and downregulation of lncRNA-MALAT1. PPE could be a promising therapy to protect against the development of DC, but further clinical studies are recommended.

Retracted: Expression of lncRNA MALAT1 through miR-144-3p in Osteoporotic Tibial Fracture Rats and Its Effect on Osteogenic Differentiation of BMSC under Traction.

[This retracts the article DOI: 10.1155/2022/2590055.].

Oncogenic lncRNA MALAT-1 recruits E2F1 to upregulate RAD51 expression and thus promotes cell autophagy and tumor growth in non-small cell lung cancer.

LncRNA MALAT-1 expression is involved in regulating activities of non-small-cell lung cancer (NSCLC) cells. This study aimed to investigate the effects of lncRNA MALAT-1 on chemosensitivity of NSCLC cells by regulating autophagy. We first validated the expression of lncRNA MALAT-1 in NSCLC cell lines. NSCLC cell lines with high lncRNA MALAT-1 expression were exposed to doxorubicin (DOX) to assess chemosensitivity. Further LncMAP database retrieval and ChIP, RIP and luciferase activity assays were conducted to explore interplay between lncRNA MALAT-1, RAD51, and E2F1. Immunofluorescence staining was performed to evaluate formation of autophagosomes in NSCLC cells. Ectopic expression and knockdown methods were used for in vitro mechanism experiments and in vivo substantiation. LncRNA MALAT-1 was overexpressed in NSCLC cells, and could promote NSCLC cell autophagy and inhibit its chemosensitivity. In vitro cell mechanism verification experiments showed that lncRNA MALAT-1 could recruit transcription factor E2F1 to bind to the promoter of RAD51, so as to promote the transcriptional expression of RAD51. In addition, cell function experiments in vitro showed that ectopically expressed lncRNA MALAT-1 promoted NSCLC cell autophagy and inhibited its chemosensitivity, while RAD51 knockdown negated its effect. Finally, in vivo animal experiments confirmed that lncRNA MALAT-1 silencing could impede the tumor growth. Taken together, this study revealed that silencing lncRNA MALAT-1 enhanced chemosensitivity of NSCLC cells by promoting autophagy, highlighting a feasible approach to prevent chemoresistance in NSCLC treatment.

QiHuangYiShen Granules Modulate the Expression of LncRNA MALAT1 and Attenuate Epithelial-Mesenchymal Transition in Kidney of Diabetic Nephropathy Rats.

QiHuangYiShen granules (QHYS), a traditional Chinese herbal medicine formula, have been used in clinical practice for treating diabetic kidney disease for several years by our team. The efficacy of reducing proteinuria and delaying the decline of renal function of QHYS has been proved by our previous studies. However, the exact mechanism by which QHYS exerts its renoprotection remains largely unknown. Emerging evidence suggests that lncRNA MALAT1 is abnormally expressed in diabetic nephropathy (DN) and can attenuate renal fibrosis by modulating podocyte epithelial-mesenchymal transition (EMT). In the present study, we aimed to explore whether QHYS could modulate lncRNA MALAT1 expression and attenuate the podocyte EMT as well as the potential mechanism related to the Wnt/β-catenin signal pathway. SD rats were fed with the high-fat-high-sucrose diet for 8 weeks and thereafter administered with 30 mg/kg streptozotocin intraperitoneally to replicate the DN model. Quality control of QHYS was performed using high-performance liquid chromatography. QHYS were orally administered at 1.25, 2.5, and 5 g/kg doses, respectively, to the DN model rats for 12 weeks. Body weight, glycated haemoglobin, blood urea nitrogen, serum creatinine, 24-h proteinuria, and kidney index were measured. The morphologic pathology of the kidney was evaluated by Hematoxylin-eosin and Masson's trichrome staining. The expression level of lncRNA MALAT1 was determined by quantitative real-time polymerase chain reaction. In addition, the expression levels of podocyte EMT protein markers and Wnt/β-catenin pathway proteins in renal tissues were evaluated by Western blotting and immunohistochemistry. The results showed that QHYS significantly reduced 24-h proteinuria, blood urea nitrogen, kidney index, and ameliorated glomerular hypertrophy and collagen fiber deposition in the kidney of DN rats. Importantly, QHYS significantly downregulated the expression level of lncRNA MALAT1, upregulated the expression of nephrin, the podocyte marker protein, downregulated the expression of desmin and FSP-1, and mesenchymal cell markers. Furthermore, QHYS significantly downregulated the expression levels of Wnt1, β-catenin, and active β-catenin. Conclusively, our study revealed that QHYS significantly reduced proteinuria, alleviated renal fibrosis, and attenuated the podocyte EMT in DN rats, which may be associated with the downregulation of lncRNA MALAT1 expression and inhibition of the Wnt/β-catenin pathway.

Baicalin suppresses the migration and invasion of breast cancer cells via the TGF-β/lncRNA-MALAT1/miR-200c signaling pathway.

Metastasis is the major cause of death and failure of cancer chemotherapy in patients with breast cancer (BC). Activation of TGF-β/lncRNA-MALAT1/miR-200c has been reported to play an essential role during the metastasis of BC cells. The present study aimed to validate the suppression of BC-cell migration and invasion by baicalin and explore its regulatory effects on the TGF-β/lncRNA-MALAT1/miR-200c signaling pathway. We found that baicalin treatment inhibited cell viability and migration and invasion. Mechanistically, baicalin treatment significantly downregulated the expression of TGF-β, ZEB1, and N-cadherin and upregulated E-cadherin on both mRNA and protein levels. Additionally, baicalin treatment significantly downregulated the expression of lncRNA-MALAT1 and upregulated that of miR-200c. Collectively, baicalin significantly suppresses cell viability, migration, and invasion of BC cells possibly by regulating the TGF-β/lncRNA-MALAT1/miR-200c pathway.

LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. The main methods of treating pancreatic cancer are surgery and chemotherapy, but the treatment efficacy is low with a poor prognosis. Immunotherapy represented by PD-1/PD-L1 has brought a milestone progress in the treatment of pancreatic cancer. However, the unique tumor microenvironment of pancreatic cancer presents challenges for immunotherapy. In addition, m6A is a common RNA modification and a potential molecular target in tumor therapy. The expression pattern of m6A in pancreatic cancer is still unclear. LncRNAs also play an essential role in pancreatic cancer development and treatment. In this study, we found that some m6A regulators were significantly elevated in pancreatic cancer and associated with the expression of PD-1/PD-L1. Moreover, we observed that METTL3 can increase the expression of PD-L1. Notably, METTL3 positively regulates the expression of lncRNA MALAT1 in pancreatic cancer cells. Strikingly, lncRNA MALAT1 increased the expression of PD-L1 in pancreatic cancer cells. This finding indicated that METTL3 regulated the expression of PD-L1 possibly via targeting lncRNA MALAT1 in pancreatic cancer cells. Lastly, MALAT1 governed the viability of pancreatic cancer cells. Taken together, lncRNA MALAT1 is involved in METTL3-mediated promotion of PD-L1 expression in pancreatic cancer.

Expression of lncRNA MALAT1 through miR-144-3p in Osteoporotic Tibial Fracture Rats and Its Effect on Osteogenic Differentiation of BMSC under Traction.

Objective To investigate the expression of lncRNA MALAT1 and miR-144-3p in osteoporotic (OP) tibial fracture rats and analyze their targeting relationship and effects on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC) under traction. Methods The OP tibial fracture model was established, and the rats were divided into a sham group and a model group. The tibial tissue of these rats was taken. BMSC of cultured rats with good growth was purchased and grouped according to the presence or absence of transfection of si-MALAT1 and miR-144-3p-mimic. The expression of MALAT1 and miR-144-3p in each group was detected. The bioinformatics website and double luciferase were used to predict the targeting relationship between MALAT1 and miR-144-3p and to detect the expression of genes related to bone differentiation (collagen I, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP)) of each component, and ALP staining and AR staining were used to detect the formation of BMSC calcium nodules. Results The levels of ALP and TRAP in the model group were higher than that in the sham group (P < 0.05). qRT-PCR results showed that the relative expression level of MALAT1 in the model group was higher than that in the sham group, and the relative expression level of miR-144-3p was lower than that in the sham group (P < 0.05). MALAT1 has a targeting relationship with miR-144-3p. qRT-PCR results showed that the relative expression level of MALAT1 in the tension-MSC group was higher than the MSC group, and the relative expression level of miR-144-3p was lower than the MSC group (P < 0.05). The expressions of collagen I, OCN, OPN, and ALP proteins in the si-MALAT1 group were higher than those of the si-NC group (P < 0.05). The results of ALP staining showed that BMSCs of the si-MALAT1 group had stronger osteogenic differentiation capacity and higher ALP activity than those of the si-NC group. The results of AR staining showed that compared with the si-NC group, the mineralization degree of cells in the si-MALAT1 group was higher, the number of calcium nodules was more, and the cells were more deeply stained. The expressions of collagen I, OCN, OPN, and ALP proteins in the miR-144-3p-mimic group were higher than the mimic-NC group (P < 0.05). ALP staining results showed that BMSCs in the miR-144-3p-mimic group had strong osteogenic differentiation capacity and high ALP activity compared with the mimic-NC group. The results of AR staining showed that, compared with the mimic-NC group, the mineralization degree of cells in the miR-144-3p-mimic group was higher, the number of calcium nodules was more and the cells were more deeply stained. Conclusion In the OP rat model with the tibial fracture, the expression of MALAT1 is upregulated and that of miR-144-3p is downregulated. MALAT1 has a targeting relationship with miR-144-3p, and downregulation of MALAT1 and upregulation of miR-144-3p can promote the osteogenic differentiation of BMSC under traction.

LncRNA MALAT1 promotes HCC metastasis through the peripheral vascular infiltration via miRNA-613: a primary study using contrast ultrasound

BackgroundThis study aimed to explore the specific pathogenesis of lncRNA MALAT1 promoting the invasion and metastasis of hepatocellular carcinoma (HCC) through peripheral blood vessels by regulating the expression of miRNA-613 molecule.MethodsThe data of 60 HCC metastatic patients and 60 HCC non-metastatic patients detected by the contrast-enhanced ultrasound (CEUS) in the Second Affiliated Hospital of Qiqihar Medical College from January 2020 to June 2021 were collected, as well as postoperatively retained HCC tissues and paired paracancer tissues (5 cm laterally from the edge of the cancer area), to study the changes of microangiogenesis in HCC tissues with CEUS. The correlation between CEUS grading and lncRNA MALAT1 in patients with HCC was analyzed through Pearson correlation analysis, lncRNA MALAT1 and miRNA-613 in HCC tissues of patients with HCC were detected by qRT-PCR, followed by the bioinformatic analysis for the relationship between lncRNA MALAT1 and miRNA-613. The Log-growing human HCC cell strain, HepG2, was selected for experiments. Adenovirus transfection knocked down lncRNA MALAT1 in HCC cells, which was divided into two groups (inhibitor-NC group and lncR-inhibitor group), followed by knocking down miRNA-613 on the basis of knocking down lncRNA MALAT1, which was divided into three groups (inhibitor-NC group, lncR-inhibitor groups, and lncR/miR613-inhibitor group). The expression of miRNA-613 and lncRNA MALAT1 in each group was detected by qRT-PCR. The migration and invasiveness of cells in each group were detected by Transwell assay.ResultsCEUS of HCC and Pearson correlation analysis showed that CEUS grading and lncRNA MALAT1 were positively correlated in patients with HCC. In HCC tissues of patients with HCC, lncRNA MALAT1 expressed high and miRNA-613 expressed low. The results of bioinformatic analysis showed the targeting of lncRNA MALAT1 and miRNA-613. Knocking down lncRNA MALAT1 could increase miRNA-613 expression significantly, and reduce the migration of HCC cells. Inhibiting miRNA-613 based on knocking down lncRNA MALAT1 could increase the survival and migration of HCC cells.ConclusionslncRNA MALAT1 can promote HCC metastasis through the peripheral vascular infiltration by inhibiting the level of MiRNA-613, which can, therefore, be used as a potential target for the treatment of HCC.

Interferon-alpha regulates expression of lncRNA MALAT1 and interferon-stimulated genes, as well as chemokine production, in primary Sjögren's syndrome.

This study aimed to explore the contribution of interferon-alpha (IFN-α) to MALAT1 expression in primary Sjögren's syndrome (pSS). Peripheral blood mononuclear cells (PBMC) from pSS patients and healthy blood donors were stimulated with recombinant human IFN-α, and the expression levels of MALAT1 and several interferon-stimulated genes (ISGs) were measured by RT-PCR, while supernatant levels of interferon-regulated chemokines were measured using multiplex cytokine immunobead assay. In this work, we found that MALAT1 expression levels were increased in IFN-α-stimulated PBMC from pSS patients and healthy controls. As expected, ISG expression levels and interferon-regulated chemokine secretion levels were higher after IFN-α stimulation. However, the fold-change values for ISG15, Ly6E, OAS1, and OASL expression levels were higher in cells from pSS patients than in controls. Similarly, PBMC from pSS patients produced higher concentrations of chemokines than those from healthy controls after IFN-α stimulation. Our data provide insights into the abnormal IFN-α-mediated regulation of the lncRNA MALAT1 in pSS. Based on an unusually high capacity of PBMC to express ISG and to produce interferon-responsive chemokines, it is likely that targeted therapies to block these molecules may be of benefit to patients with pSS.

Baihe Dihuang (Lilium Henryi Baker and Rehmannia Glutinosa) decoction attenuates somatostatin interneurons deficits in prefrontal cortex of depression via miRNA-144–3p mediated GABA synthesis and release

Ethnopharmacological relevanceBaihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years. Aim of the studyLBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron. Materials and methodsIn this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and Western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization. ResultsIn the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144–3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144–3p expression. ConclusionsThese findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144–3p mediated GABA synthesis and release.

Downregulation of the long non-coding RNA MALAT1 in tenofovir-treated pregnant women with hepatitis B virus infection promotes immune recovery of natural killer cells via the has-miR-155-5p/HIF-1α axis

BackgroundCurrently, tenofovir disoproxil fumarate (TDF) treatment in pregnant women with hepatitis B virus (HBV) infection in the second trimester of pregnancy to reduce the HBV DNA load and block the mother-to-child transmission of HBV has become a consensus. An increasing number of studies have shown that lncRNAs play an important role in immune regulation; however, there are only a few studies on how lncRNAs affect the immune function of TDF-treated pregnant women with HBV infection. MethodsThe peripheral blood of pregnant women with HBV infection was collected before and after TDF treatment for whole-transcriptome sequencing; the differential expression of lncRNA MALAT1 in PBMCs and natural killer (NK) cells was verified by qRT-PCR. ELISA and flow cytometry were used to detect the effect of MALAT1 on NK-92 cells on IFN-γ secretion. Dual-luciferase reporter, qRT-PCR, and western blot analyses were used to verify the relationship between the expression levels of MALAT1, has-miR-155-5p and HIF-1α. ResultsAfter TDF treatment, the MALAT1 expression in the PBMCs of pregnant women with HBV infection, especially in NK cells, was significantly reduced. MALAT1 overexpression decreased IFN-γ secretion in NK-92 cells, while IFN-γ secretion increased after MALAT1 knockdown. Mechanistically, we identified MALAT1 as a competitive endogenous RNA that regulates HIF-1α expression by sponging has-miR-155-5p. Low HIF-1α expression resulted in increased IFNG expression in, and IFN-γ secretion by, NK cells. ConclusionsThus, MALAT1 may play an important role in NK cell-mediated immunity in TDF-treated pregnant women with HBV infection by regulating the has-miR-155-5p/HIF-1α axis.

Long Non-coding RNA MALAT1 Is Depleted With Age in Skeletal Muscle in vivo and MALAT1 Silencing Increases Expression of TGF-β1 in vitro

Long non-coding RNAs (lncRNAs) are thought to function as “sponges” for microRNAs, but a role for such competing endogenous RNAs (ceRNAs) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4–6 months) and aged (22–24) male and female mice the expression of lncRNA MALAT1, which is predicted in silico to bind the senescence-associated microRNA miR-34a-5p. Results indicate a significant decrease in lncRNA MALAT1 expression in mouse skeletal muscle with age that coincides with an age-related increase in miR-34a-5p expression. In vitro studies using mouse C2C12 myoblasts demonstrate that MALAT1 silencing using siRNA increases miR-34a expression, consistent with a role for MALAT1 as an inhibitor of miR-34a-5p activity. Levels of reactive oxygen species (ROS) are known to increase in muscle with age, and so we treated C2C12 cells with hydrogen peroxide (10 and 100 μM) to examine changes in MALAT1 expression. MALAT1 expression decreased significantly with H2O2 treatment, but this effect was attenuated with p53 siRNA. Finally, miR-34a-5p is implicated in tissue fibrosis, and so we assessed the expression of TGF-β1 after MALAT1 silencing. MALAT1 siRNA significantly increased the expression of TGF-β1 in C2C12 cells. These findings suggest that age-related fibrosis and muscle atrophy mediated by ROS may result at least in part from an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. Crosstalk between MALAT1 and miR-34a may therefore represent a therapeutic target for improving muscle function with aging.

Expression of LncRNA-MALAT1 in Peripheral Blood of Patients with Acute Myeloid Leukemia Sepsis and Its Clinical Significance

To analyze the expression of lncRNA-MALAT1 in peripheral blood of patients with acute myeloid leukemia (AML) sepsis and explore its clinical significance. From March 2018 to March 2019, 95 confirmed AML patients including 43 sepsis infected cases and 52 uninfected cases were selected for treatment in the Department of Oncology and Hematology, The First People's Hospital of Longquanyi District. Their peripheral blood samples were taken as study samples, and the blood samples from 50 healthy people were used as control. RT-qPCR was used to detect lncRNA-MALAT1 expression level in samples from healthy group, uninfected group, and sepsis group. The correlation between lncRNA-MALAT1 expression level and clinical characteristics and prognosis of AML patients with sepsis were analyzed. The expression level of lncRNA-MALAT1 in the sepsis group was significantly up-regulated compared with the healthy group and uninfected group (P<0.05), while there was no significant difference between the healthy group and uninfected group (P>0.05). In AML patients with sepsis, the expression of lncRNA-MALAT1 was associated with clinical characteristics such as NCCN risk classification, white blood cell count, hemoglobin and so on. The overall survival rate of high lncRNA-MALAT1 expression group was significantly lower than that of low expression group (χ2=23.157, P=0.002). COX regression analysis showed that lncRNA-MALAT1 could be an independent prognostic factor for AML sepsis patients. The up-regulated expression of lncRNA-MALAT1 is closely related to the clinical characteristics and survival rate, and is an independent prognostic factor for AML sepsis patients. LncRNA-MALAT1 is expected to become a new diagnostic marker and therapeutic target for AML sepsis.

Propofol Downregulates lncRNA MALAT1 to Alleviate Cerebral Ischemia-Reperfusion Injury.

Propofol (PPF) is reported to play a protective role in ischemia/reperfusion (I/R) injury, including cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the mechanism by which PPF ameliorates CIRI. Kunming mice were used to establish the middle cerebral artery occlusion (MCAO)/reperfusion mouse model in vivo. PPF pre-treatment was performed before CIRI. Lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) levels were detected to evaluate the tissue injury. PC12 cells were exposed to hypoxia/reoxygenation (H/R) to construct the in vitro CIRI model, and PC12 cells were pre-treated with PPF before H/R. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of lncRNA MALAT1 and miR-182-5p. Flow cytometry was used to detect the apoptosis of PC12 cells. Bioinformatics analysis, qRT-PCR, dual-luciferase reporter gene experiments, and RNA immunoprecipitation (RIP) experiments were performed to predict and validate the targeting relationship between MALAT1 and miR-182-5p. Western blot was used to detect Toll-like receptor 4 (TLR4) expression at protein level. PPF pre-treatment remarkably inhibited LDH and CPK levels in the serum of the mice with CIRI, and reduced the apoptosis of PC12 cells exposed to H/R. Besides, PPF pre-treatment markedly suppressed MALAT1 expression in both in vivo and in vitro models and upregulated miR-182-5p expression. MiR-182-5p was validated to be a downstream target gene of MALAT1, and MALAT1 could increase the expression of TLR4 by suppressing miR-182-5p. The effects of PPF on the injury of the mice brain and PC12 cells were partly counteracted by the restoration of MALAT1. PPF protects the brain against I/R-induced injury by regulating MALAT1/miR-182-5p/TLR4 axis.

LncRNA-Malat1 down-regulates miR-211-5p expression to promote neuronal damage from cerebral ischemia reperfusion injury

Based on the previous studies, this study was carried out to explore the interaction of LncRNA-Malat1/miR-211-5p in cerebral ischemia reperfusion injury (CIRI). Firstly, the expression changes of LncRNA-MALAT1 and miR-211-5p in ischemia patients’ blood were determined, and the binding sites of them were predicted by bioinformatics. Furthermore, middle cerebral artery occlusion/reperfusion (MCAO/R) injury model was established in adult male SD rats, and primary neuronal oxygen-glucose deprivation/reoxygen-glucose reoxygenation (OGD/R) was established in vitro. The results showed that LncRNA-MALAT1 was significantly up-regulated and miR-211-5p down-regulated in the peripheral blood of patients with ischemic stroke, and the expression changes were negatively correlated. Bioinformatics prediction results showed that LncRNA-MALAT1 had a binding site with miR-211-5p. We also found that LncRNA-Malat1 was significantly up-regulated while miR-211-5p down-regulated in rat cortex tissue and primary neurons treated with OGD/R. In addition, lentivirus interfered with LV-Malat1-RNAi decreased the expression of LncRNA-Malat1 and promoted the up-regulation of miR-211-5p. Combination of LV-Malat1-RNAi and miR-211-5p inhibitor significantly reversed the protective effect of down-regulation of LncRNA-Malat1. Inhibition of LncRNA-Malat1 expression alleviated the neurological deficit score after MCAO/R, improved histopathological damage, and reduced the size of cerebral infarction. Combined administration of LV-Malat1-RNAi + Antagomir-211-5p reversed these effects above. In short, our data suggest that LncRNA-Malat is involved in the occurrence and development of cerebral ischemia reperfusion injury by acting on miR-211-5p and is then regulating the expression of COX-2.